DOCSLIB.ORG

Tracing the Structural Evolution of Eukaryotic ATP Binding Cassette Transporter Superfamily

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tracing the Structural Evolution of Eukaryotic ATP Binding Cassette Transporter Superfamily Tracing the structural evolution of eukaryotic ATP binding cassette transporter superfamily The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Xiong, Jie, Jinmei Feng, Dongxia Yuan, Jun Zhou, and Wei Miao. 2015. “Tracing the structural evolution of eukaryotic ATP binding cassette transporter superfamily.” Scientific Reports 5 (1): 16724. doi:10.1038/srep16724. http://dx.doi.org/10.1038/srep16724. Published Version doi:10.1038/srep16724 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845332 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA www.nature.com/scientificreports OPEN Tracing the structural evolution of eukaryotic ATP binding cassette transporter superfamily Received: 12 August 2015 1 1 1 2 1 Accepted: 19 October 2015 Jie Xiong , Jinmei Feng , Dongxia Yuan , Jun Zhou & Wei Miao Published: 18 November 2015 The ATP binding cassette (ABC) transporters superfamily is one of the largest classes of membrane proteins. The core of the ABC transporter protein is composed of transmembrane domains (TMDs) and nucleotide binding domains (NBD). Eukaryotes ABC transporters are classified into seven main families (ABCA to ABCG) based on sequence similarity and domain organizations. With different domain number and domain organizations, eukaryote ABC transporters show diverse structures: the single structure (NBD or TMD), the ABC2 structure (NBD-NBD), the half structure (TMD-NBD or NBD-TMD) and the full structure (TMD-NBD-TMD-NBD or NBD-TMD-NBD-TMD). However, studies on how various ABC transporter gene structures evolved is still absent. Therefore, in this study, we comprehensively investigated the structural evolution of eukaryotic ABC transporters. The seven eukaryote ABC transporter families (A to G) fell into three groups: A&G group, B,C&D group and E&F group. There were at least four times the number of NBD and TMD fusion events in the origin of the half structure transporter. Two fusion modes were found in the full and ABC2 structure origination. Based on these findings, we present a putative structural evolutionary path of eukaryote ABC transporters that will increase our understanding on their origin, divergence and function. The movement of molecules into and out of cells is mediated by cell membranes, in many cases by specialized membrane proteins known as transporters. Integral membrane ATP Binding Cassette (ABC) transporters are ubiquitous in all three domains of life and form one of the largest classes of membrane proteins1,2. Through the hydrolysis of ATP to generate energy, ABC transporters move a wide variety of substrates across membranes, including ions, sugars, amino acids, polypeptides, toxic metabolites, xenobiotics, and even drugs and toxins. A typical structure of eukaryotic ABC transporters consists of two conserved domains: a transmembrane domain (TMD) and a nucleotide binding domain (NBD)3. TMDs typically contain several transmembrane helices, and NBDs have several conserved motifs: Walker A motif, Q loop, Signature motif and Walker B motif1,4. According to domain organizations and primary sequence homology, eukaryotic ABC transporters have been classified into seven families, from ABCA to ABCG5–12. Members of the seven ABC transporter families are widely distributed in eukaryotes. In the ABC transporter superfamily, the sizes of the genes vary drastically across species, and can possess more than a hundred copies in some organisms such as the brassicacean Arabidopsis thaliana13 and the ciliate Tetrahymena thermophila14. Despite being called transporters, two eukaryotic ABC transporter families (ABCE and ABCF) do not function as transporters but are involved in other cellular processes including ribonuclease inhibition and translational control15,16, mainly because they no longer carry TMD domains. The structures of ABC transporters are diverse owing to their different domain compositions. A trans- porter protein with NBD-TMD-NBD-TMD or TMD-NBD-TMD-NBD organization is designated as a full transporter (or full structure)17; A half transporter (or half structure) is composed of only one TMD and one NBD, with either NBD-TMD or TMD-NBD organization. Some transporters encoded with 1Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, PR China. 2Department of Organismic and Evolutionary Biology, Harvard University, MA 02138, USA. Correspondence and requests for materials should be addressed to J.Z. (email: [email protected]) or W.M. (email: [email protected]) SCIENTIFIC REPORTS | 5:16724 | DOI: 10.1038/srep16724 1 www.nature.com/scientificreports/ Figure 1. Illustration of the different structures in the ABC transporter superfamily. Full structure represents the ABC transporter gene that encodes two TMDs and two NBDs; Half structure represents the ABC transporter gene that encodes one TMD and one NBD; Single structure represents the ABC transporter gene with a single TMD or NBD; ABC2 structure represents the ABC transporter gene with only two NBDs. The families possessing certain structures are listed on the right. only a single TMD or NBD are defined as single domain structure. In non-transporter ABC proteins, only NBDs are present at both the N- and the C-terminus. Such cases with NBD-NBD organization is referred to as the ABC2 structure. Most previous work on ABC transporter genes focused on either function18 or phylogeny7,10,11,13,14,19. Two large-scale analyses of ABC transporters were conducted across multiple kingdoms. One study investigated ABC transporters in 20 model organisms with the objective of identifying the function of proteins based on sequence similarity using a simple method known as the “function transfer rule”20. The other study described two large novel clusters of bacterial multidrug transporters related to the eukaryotic ABCB and ABCC families, and proposed an evolutionary hypothesis that NBDs of many transporter families derive from the common ancestor of prokaryotes and eukaryotes21. Nevertheless, a comprehensive analysis of how various ABC transporter gene structures evolved is still absent. The rapidly accumulating genomic data of diverse species have provided an excellent opportunity to infer the structural evolution of this ancient gene superfamily. Here, we investigated the phylogeny of the ABC transporter superfamily using proteins from diverse eukaryote kingdoms, analyzed domain features, and proposed a detailed path that traces the evolution of the diverse structures of the ABC transporter superfamily. Results Distribution of ABC transporters. In the present study, ABC transporters were identified in 79 evolutionarily diverse eukaryotic genomes (Table S1) that are representatives of eight eukaryotes lineages - alveolata, amoebozoa, euglenozoa, fungi, metazoa, fornicata, choanoflagellida and viridiplantae, and 2302 prokaryote genomes (Table S2) including those of both bacteria and archaea. The ABC transporter is a large superfamily with many families. Proteins in different families may have low sequence similari- ties thus increasing the difficulty to identify these proteins. To avoid this, members in all known eukar- yotic ABC transporter families were used as seed proteins and searched against all the selected genomes by BLASTP using a very relaxed E-value cutoff (10). All the BLASTP hits (ABC transporter candidates) were then scanned using more sensitive profile-based domain searching. Proteins with an NBD domain were regarded as ABC transporters. Domain compositions and gene structures were also investigated. We found that, in prokaryotes, the ABC genes mainly encode TMD or NBD single structure, followed by TMD-NBD half structure and ABC2 NBD-NBD structure. We also discovered NBD-TMD half struc- ture and TMD-NBD-TMD-NBD full structure (Fig. 1). Our findings are consistent with previous studies that prokaryotic ABC proteins predominantly contain single and half structures. By contrast, eukaryotes mainly contain half and full structures (Fig. 1). It is therefore likely that ABC transporters have under- gone an evolutionary path from simple to complex structures (i.e. from single to half or ABC2 structure, then from half to full structure). All seven eukaryote ABC transporter families are present in eukaryotic species (Table S1) suggesting they may have originated before the last eukaryotic common ancestor (LECA). TMD-NBD half structure was found in ABCA, ABCB and ABCD families, and TMD-NBD-TMD-NBD full structure was found in ABCA, ABCB and ABCC families. However, both NBD-TMD half structure and NBD-TMD-NBD-TMD SCIENTIFIC REPORTS | 5:16724 | DOI: 10.1038/srep16724 2 www.nature.com/scientificreports/ Family ABCA ABCB ABCC ABCD ABCE ABCF ABCG ABCA 38% 25% 23% 21% 22% 22% 26% ABCB – 47% 30% 25% 22% 24% 25% ABCC – – 37% 24% 19% 21% 22% ABCD – – – 41% 20% 21% 21% ABCE – – – – 37% 20% 21% ABCF – – – – – 31% 23% ABCG – – – – – – 37% Table 1. Mean identities among the NBD sequences of seven ABC transporter families. full structure were only found in the ABCG family. NBD-NBD ABC2 structure was only detected in ABCE and ABCF families (Fig. 1 and Table S1). Finally, there were sporadic genes showing half or single structures in the ABCC family, single structures in ABCE, ABCF and unknown families (no high-score
Load more

Recommended publications
  • ABCB7 Gene ATP Binding Cassette Subfamily B Member 7
    ABCB7 gene ATP binding cassette subfamily B member 7 Normal Function The ABCB7 gene provides instructions for making a protein known as an ATP-binding cassette (ABC) transporter. ABC transporter proteins carry many types of molecules across membranes in cells. The ABCB7 protein is located in the inner membrane of cell structures called mitochondria. Mitochondria are involved in a wide variety of cellular activities, including energy production, chemical signaling, and regulation of cell growth and division. In the mitochondria of developing red blood cells (erythroblasts), the ABCB7 protein plays a critical role in the production of heme. Heme contains iron and is a component of hemoglobin, the protein that carries oxygen in the blood. The ABCB7 protein is also involved in the formation of certain proteins containing clusters of iron and sulfur atoms (Fe-S clusters). Researchers suspect that the ABCB7 protein transports Fe-S clusters from mitochondria, where they are formed, to the surrounding cellular fluid (cytosol), where they can be incorporated into proteins. Overall, researchers believe that the ABCB7 protein helps maintain an appropriate balance of iron (iron homeostasis) in developing red blood cells. Health Conditions Related to Genetic Changes X-linked sideroblastic anemia and ataxia At least three mutations in the ABCB7 gene have been identified in people with X-linked sideroblastic anemia with ataxia. Each of these mutations changes a single protein building block (amino acid) in the ABCB7 protein, slightly altering its structure. These changes disrupt the protein's usual role in heme production and iron homeostasis. Anemia results when heme cannot be produced normally, and therefore not enough hemoglobin is made.
    [Show full text]
  • Structures and Functions of Mitochondrial ABC Transporters
    ATP-binding cassette transporters: from mechanism to organism 943 Structures and functions of mitochondrial ABC transporters Theresia A. Schaedler*, Belinda Faust†, Chitra A. Shintre†, Elisabeth P. Carpenter†, Vasundara Srinivasan‡, Hendrik W. van Veen§ and Janneke Balk1 *Department of Biological Chemistry and Crop Protection, Rothamsted Research, West Common, Harpenden, AL5 2JQ, U.K. †Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, U.K. ‡LOEWE center for synthetic microbiology (SYNMIKRO) and Philipps University, D-35043 Marburg, Germany §Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, U.K. John Innes Centre and University of East Anglia, Colney Lane, Norwich, NR4 7UH, U.K. Abstract A small number of physiologically important ATP-binding cassette (ABC) transporters are found in mitochondria. Most are half transporters of the B group forming homodimers and their topology suggests they function as exporters. The results of mutant studies point towards involvement in iron cofactor biosynthesis. In particular, ABC subfamily B member 7 (ABCB7) and its homologues in yeast and plants are required for iron-sulfur (Fe-S) cluster biosynthesis outside of the mitochondria, whereas ABCB10 is involved in haem biosynthesis. They also play a role in preventing oxidative stress. Mutations in ABCB6 and ABCB7 have been linked to human disease. Recent crystal structures of yeast Atm1 and human ABCB10 have been key to identifying substrate-binding sites and transport mechanisms. Combined with in vitro and in vivo studies, progress is being made to find the physiological substrates of the different mitochondrial ABC transporters. Sequence analysis of mitochondrial ABC The ABCB7 group, which includes the ABC transporters transporters of the mitochondria Atm1 in yeast and ATM3 in Arabidopsis, Mitochondria of most eukaryote species harbour 2–4 can be found in virtually all eukaryotic species.
    [Show full text]
  • ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center
    University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2008 ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Chemicals and Drugs Commons, and the Medical Sciences Commons Recommended Citation Fukuda, Yu , "ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters" (2008). Theses and Dissertations (ETD). Paper 345. http://dx.doi.org/10.21007/etd.cghs.2008.0100. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Interdisciplinary Program Research Advisor John D. Schuetz, Ph.D. Committee Linda Hendershot, Ph.D. James I. Morgan, Ph.D. Anjaparavanda P. Naren, Ph.D. Jie Zheng, Ph.D. DOI 10.21007/etd.cghs.2008.0100 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/345 ABCB6 IS A PORPHYRIN TRANSPORTER WITH A NOVEL TRAFFICKING SIGNAL THAT
    [Show full text]
  • Genome-Wide Identification of Whole ATP-Binding Cassette (ABC)
    Jeong et al. BMC Genomics 2014, 15:651 http://www.biomedcentral.com/1471-2164/15/651 RESEARCH ARTICLE Open Access Genome-wide identification of whole ATP-binding cassette (ABC) transporters in the intertidal copepod Tigriopus japonicus Chang-Bum Jeong1, Bo-Mi Kim2, Jae-Seong Lee2* and Jae-Sung Rhee3* Abstract Backgrounds: The ATP-binding cassette (ABC) transporter superfamily is one of the largest transporter gene families and is observed in all animal taxa. Although a large set of transcriptomic data was recently assembled for several species of crustaceans, identification and annotation of the large ABC transporter gene family have been very challenging. Results: In the intertidal copepod Tigriopus japonicus, 46 putative ABC transporters were identified using in silico analysis, and their full-length cDNA sequences were characterized. Phylogenetic analysis revealed that the 46 T. japonicus ABC transporters are classified into eight subfamilies (A-H) that include all the members of all ABC subfamilies, consisting of five ABCA, five ABCB, 17 ABCC, three ABCD, one ABCE, three ABCF, seven ABCG, and five ABCH subfamilies. Of them, unique isotypic expansion of two clades of ABCC1 proteins was observed. Real-time RT-PCR-based heatmap analysis revealed that most T. japonicus ABC genes showed temporal transcriptional expression during copepod development. The overall transcriptional profile demonstrated that half of all T. japonicus ABC genes were strongly associated with at least one developmental stage. Of them, transcripts TJ-ABCH_88708 and TJ-ABCE1 were highly expressed during all developmental stages. Conclusions: The whole set of T. japonicus ABC genes and their phylogenetic relationships will provide a better understanding of the comparative evolution of essential gene family resources in arthropods, including the crustacean copepods.
    [Show full text]
  • ABCD3 (F-1): Sc-514728
    SANTA CRUZ BIOTECHNOLOGY, INC. ABCD3 (F-1): sc-514728 BACKGROUND APPLICATIONS The peroxisomal membrane contains several ATP-binding cassette (ABC) ABCD3 (F-1) is recommended for detection of ABCD3 of human origin by transporters, ABCD1-4 that are known to be present in the human peroxisome Western Blotting (starting dilution 1:100, dilution range 1:100-1:1000), membrane. All four proteins are ABC half-transporters, which dimerize to form immunoprecipitation [1-2 µg per 100-500 µg of total protein (1 ml of cell an active transporter. A mutation in the ABCD1 gene causes X-linked adreno- lysate)], immunofluorescence (starting dilution 1:50, dilution range 1:50- leukodystrophy (X-ALD), a peroxisomal disorder which affects lipid storage. 1:500) and solid phase ELISA (starting dilution 1:30, dilution range 1:30- ABCD2 in mouse is expressed at high levels in the brain and adrenal organs, 1:3000). which are adversely affected in X-ALD. The peroxisomal membrane comprises Suitable for use as control antibody for ABCD3 siRNA (h): sc-41147, ABCD3 two quantitatively major proteins, PMP22 and ABCD3. ABCD3 is associated shRNA Plasmid (h): sc-41147-SH and ABCD3 shRNA (h) Lentiviral Particles: with irregularly shaped vesicles which may be defective peroxisomes or per- sc-41147-V. oxisome precursors. ABCD1 localizes to peroxisomes. ABCB7 is a half-trans- porter involved in the transport of heme from the mitochondria to the cytosol. Molecular Weight of ABCD3: 75 kDa. Positive Controls: HeLa whole cell lysate: sc-2200, SH-SY5Y cell lysate: REFERENCES sc-3812 or Caco-2 cell lysate: sc-2262.
    [Show full text]
  • Three Hundred Twenty-Six Genetic Variations in Genes Encoding Nine Members of ATP-Binding Cassette, Subfamily B (ABCB/MDR/TAP), in the Japanese Population
    4600/38J Hum Genet (2002) 47:38–50 N. Matsuda et al.: © Jpn EGF Soc receptor Hum Genet and osteoblastic and Springer-Verlag differentiation 2002 ORIGINAL ARTICLE Susumu Saito · Aritoshi Iida · Akihiro Sekine Yukie Miura · Chie Ogawa · Saori Kawauchi Shoko Higuchi · Yusuke Nakamura Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population Received: September 18, 2001 / Accepted: November 2, 2001 Abstract We screened DNAs from 48 Japanese individuals domain (Hyde et al. 1990). ABC proteins constitute a super- for single-nucleotide polymorphisms (SNPs) in nine genes family consisting of eight subfamilies: ABC1, MDR/TAP, encoding components of ATP-binding cassette subfamily CFTR/MRP, ALD, OABP, GCN20, WHITE, and ANSA B (ABCB/MDR/TAP) by directly sequencing the entire (Kerb et al. 2001; Human ABC gene nomenclature applicable genomic regions except for repetitive elements. committee, http://www.gene.ucl.ac.uk/nomenclature/ This approach identified 297 SNPs and 29 insertion/deletion genefamily/abc.html). polymorphisms among the nine genes. Of the 297 SNPs, 50 Members of the MDR/TAP subfamily include the were identified in the ABCB1 gene, 14 in TAP1, 35 in ATP-binding cassette, subfamily B (ABCB) and the TAP2, 48 in ABCB4, 13 in ABCB7, 21 in ABCB8, 21 in transporter associated with antigen processing (TAP). The ABCB9, 13 in ABCB10, and 82 in ABCB11. Thirteen were ABCB1 [ATP-binding cassette, subfamily B, member 1, located in 5Ј flanking regions, 237 in introns, 37 in exons, also called multidrug resistance (MDR)-1] gene encodes P- and 10 in 3Ј flanking regions.
    [Show full text]
  • Transcriptional and Post-Transcriptional Regulation of ATP-Binding Cassette Transporter Expression
    Transcriptional and Post-transcriptional Regulation of ATP-binding Cassette Transporter Expression by Aparna Chhibber DISSERTATION Submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmaceutical Sciences and Pbarmacogenomies in the Copyright 2014 by Aparna Chhibber ii Acknowledgements First and foremost, I would like to thank my advisor, Dr. Deanna Kroetz. More than just a research advisor, Deanna has clearly made it a priority to guide her students to become better scientists, and I am grateful for the countless hours she has spent editing papers, developing presentations, discussing research, and so much more. I would not have made it this far without her support and guidance. My thesis committee has provided valuable advice through the years. Dr. Nadav Ahituv in particular has been a source of support from my first year in the graduate program as my academic advisor, qualifying exam committee chair, and finally thesis committee member. Dr. Kathy Giacomini graciously stepped in as a member of my thesis committee in my 3rd year, and Dr. Steven Brenner provided valuable input as thesis committee member in my 2nd year. My labmates over the past five years have been incredible colleagues and friends. Dr. Svetlana Markova first welcomed me into the lab and taught me numerous laboratory techniques, and has always been willing to act as a sounding board. Michael Martin has been my partner-in-crime in the lab from the beginning, and has made my days in lab fly by. Dr. Yingmei Lui has made the lab run smoothly, and has always been willing to jump in to help me at a moment’s notice.
    [Show full text]
  • Mitochondrial ABC Proteins in Health and Disease
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1787 (2009) 681–690 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbabio Mitochondrial ABC proteins in health and disease Ariane Zutz a, Simone Gompf a, Hermann Schägger b, Robert Tampé a,⁎ a Institute of Biochemistry, Biocenter, Goethe-University, Max-von-Laue-Str. 9, D-60348 Frankfurt a.M., Germany b Gustav-Embden-Zentrum of Biological Chemistry, Medical School, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt a.M., Germany article info abstract Article history: ABC transporters represent one of the largest families of membrane proteins that are found in all three phyla Received 23 December 2008 of life. Mitochondria comprise up to four ABC systems, ABCB7/ATM1, ABCB10/MDL1, ABCB8 and ABCB6. Received in revised form 12 February 2009 These half-transporters, which assemble into homodimeric complexes, are involved in a number of key Accepted 13 February 2009 cellular processes, e.g. biogenesis of cytosolic iron–sulfur clusters, heme biosynthesis, iron homeostasis, Available online 24 February 2009 multidrug resistance, and protection against oxidative stress. Here, we summarize recent advances and emerging themes in our understanding of how these ABC systems in the inner and outer mitochondrial Keywords: fi Heme biosynthesis membrane ful ll their functions in important (patho) physiological processes, including
    [Show full text]
  • The Putative Mitochondrial Protein ABCB6
    Shifting the Paradigm: The Putative Mitochondrial Protein ABCB6 Resides in the Lysosomes of Cells and in the Plasma Membrane of Erythrocytes Katalin Kiss, Anna Brozik, Nora Kucsma, Alexandra Toth, Melinda Gera, Laurence Berry, Alice Vallentin, Henri Vial, Michel Vidal, Gergely Szakacs To cite this version: Katalin Kiss, Anna Brozik, Nora Kucsma, Alexandra Toth, Melinda Gera, et al.. Shifting the Paradigm: The Putative Mitochondrial Protein ABCB6 Resides in the Lysosomes of Cells and in the Plasma Membrane of Erythrocytes. PLoS ONE, Public Library of Science, 2012, 7 (5), pp.e37378. 10.1371/journal.pone.0037378. hal-02309092 HAL Id: hal-02309092 https://hal.archives-ouvertes.fr/hal-02309092 Submitted on 25 May 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License Shifting the Paradigm: The Putative Mitochondrial Protein ABCB6 Resides in the Lysosomes of Cells and in the Plasma Membrane of Erythrocytes Katalin Kiss1, Anna Brozik1, Nora Kucsma1, Alexandra Toth1, Melinda Gera1,
    [Show full text]
  • Hedgehog-GLI Signalling Promotes Chemoresistance Through The
    www.nature.com/scientificreports OPEN Hedgehog‑GLI signalling promotes chemoresistance through the regulation of ABC transporters in colorectal cancer cells Agnese Po1, Anna Citarella1, Giuseppina Catanzaro2, Zein Mersini Besharat2, Sofa Trocchianesi1, Francesca Gianno1, Claudia Sabato2, Marta Moretti2, Enrico De Smaele2, Alessandra Vacca2, Micol Eleonora Fiori3 & Elisabetta Ferretti2,4* Colorectal cancer (CRC) is a leading cause of cancer death. Chemoresistance is a pivotal feature of cancer cells leading to treatment failure and ATP-binding cassette (ABC) transporters are responsible for the efux of several molecules, including anticancer drugs. The Hedgehog-GLI (HH-GLI) pathway is a major signalling in CRC, however its role in chemoresistance has not been fully elucidated. Here we show that the HH-GLI pathway favours resistance to 5-fuorouracil and Oxaliplatin in CRC cells. We identifed potential GLI1 binding sites in the promoter region of six ABC transporters, namely ABCA2, ABCB1, ABCB4, ABCB7, ABCC2 and ABCG1. Next, we investigated the binding of GLI1 using chromatin immunoprecipitation experiments and we demonstrate that GLI1 transcriptionally regulates the identifed ABC transporters. We show that chemoresistant cells express high levels of GLI1 and of the ABC transporters and that GLI1 inhibition disrupts the transporters up-regulation. Moreover, we report that human CRC tumours express high levels of the ABCG1 transporter and that its expression correlates with worse patients’ prognosis. This study identifes a new mechanism where HH‑GLI signalling regulates CRC chemoresistance features. Our results indicate that the inhibition of Gli1 regulates the ABC transporters expression and therefore should be considered as a therapeutic option in chemoresistant patients. Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide and is characterized by resistance mechanisms that lead to disease progression 1.
    [Show full text]
  • Mitoneet Regulates Mitochondrial Iron Homeostasis Interacting With
    bioRxiv preprint doi: https://doi.org/10.1101/330084; this version posted May 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 TiTle: mitoNEET Regulates Mitochondrial Iron Homeostasis Interacting with 2 Transferrin Receptor 3 4 Running Title: mitoNEET Regulates Mitoiron Homeostasis 5 6 Key words: mitochondrial iron; protein-protein interaction; reactive oxygen species; 7 mitochondrial respiration; cardiac dysfunction 8 9 Takaaki Furihata1, Shingo Takada1, Satoshi Maekawa1, Wataru Mizushima1, Masashi 10 Watanabe2, Hidehisa Takahashi2, Arata Fukushima1, Masaya Tsuda1, Junichi 11 Matsumoto1, Naoya Kakutani1, Takashi Yokota1, Shouji Matsushima1,3, Yutaro Otsuka4, 12 Masaki Matsumoto5, Keiichi I. Nakayama5, Junko Nio-Kobayashi6, Toshihiko Iwanaga6, 13 Hisataka Sabe4, Shigetsugu Hatakeyama2, Hiroyuki Tsutsui1,3, and Shintaro Kinugawa1,a 14 15 1 Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of 16 Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan 17 2 Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, 18 Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan 19 3 Department of Cardiovascular Medicine, Kyushu University Graduate School of 20 Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan 21 4 Department of Molecular Biology, Faculty of Medicine and Graduate School of 22 Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan 23 5 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, 24 Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan bioRxiv preprint doi: https://doi.org/10.1101/330084; this version posted May 24, 2018.
    [Show full text]
  • Perkinelmer Genomics to Request the Saliva Swab Collection Kit for Patients That Cannot Provide a Blood Sample As Whole Blood Is the Preferred Sample
    Autism and Intellectual Disability TRIO Panel Test Code TR002 Test Summary This test analyzes 2429 genes that have been associated with Autism and Intellectual Disability and/or disorders associated with Autism and Intellectual Disability with the analysis being performed as a TRIO Turn-Around-Time (TAT)* 3 - 5 weeks Acceptable Sample Types Whole Blood (EDTA) (Preferred sample type) DNA, Isolated Dried Blood Spots Saliva Acceptable Billing Types Self (patient) Payment Institutional Billing Commercial Insurance Indications for Testing Comprehensive test for patients with intellectual disability or global developmental delays (Moeschler et al 2014 PMID: 25157020). Comprehensive test for individuals with multiple congenital anomalies (Miller et al. 2010 PMID 20466091). Patients with autism/autism spectrum disorders (ASDs). Suspected autosomal recessive condition due to close familial relations Previously negative karyotyping and/or chromosomal microarray results. Test Description This panel analyzes 2429 genes that have been associated with Autism and ID and/or disorders associated with Autism and ID. Both sequencing and deletion/duplication (CNV) analysis will be performed on the coding regions of all genes included (unless otherwise marked). All analysis is performed utilizing Next Generation Sequencing (NGS) technology. CNV analysis is designed to detect the majority of deletions and duplications of three exons or greater in size. Smaller CNV events may also be detected and reported, but additional follow-up testing is recommended if a smaller CNV is suspected. All variants are classified according to ACMG guidelines. Condition Description Autism Spectrum Disorder (ASD) refers to a group of developmental disabilities that are typically associated with challenges of varying severity in the areas of social interaction, communication, and repetitive/restricted behaviors.
    [Show full text]